Aortic aneurysms and dissections (AAD) carry significantly high morbidity and mortality. Unfortunately, no clinically proven medication is available to prevent disease progression. There is a critical need to develop effective pharmacological strategies to treat the disease. This project focuses on sporadic AAD which account for more than 80% of cases. One of the significant features of sporadic AAD is progressive smooth muscle cell (SMC) dysfunction and depletion, for which the underlying molecular mechanisms are poorly understood. The aortic wall is constantly exposed to various insults such as hemodynamic disturbance, inflammatory factors and metabolic stress. These factors can interfere with normal cellular functions. Protein biosynthesis and folding in the endoplasmic reticulum (ER) is particularly vulnerable to stress. Disruption in this process causes protein misfolding and ER stress, which in turn can amplify stress and induce a cellular inflammatory response that leads to cell dysfunction, dedifferentiation, and even cell death. The overall objectives of this application are to determine the role of ER stress and ER stress sensor STING in aortic destruction, and the extent to which this mechanism represents a therapeutic target against AAD. We propose 3 specific aims. In Aim 1, we will investigate the mechanisms by which the ER stress-STING pathway induces SMC dysfunction and depletion. Aim 1A, we will test the hypothesis that the ER stress-STING pathway, through IRF3, inhibits myocardin/SRF-mediated transcription of SMC genes, and induces SMC dedifferentiation and dysfunction. Aim 1B, we will test the hypothesis that the ER stress-STING pathway promotes RIP3/ MLKL phosphorylation/activation and induces SMC necroptosis. In Aim 2, we will define the role of the ER stress-STING pathway in biomechanical failure and AAD formation in vivo. Aim 2A, we will test the hypothesis that ER stress pro- motes SMC dedifferentiation and depletion, and thus renders the aortic wall vulnerable to hemodynamic stress and susceptible to AAD formation. Aim 2B, we will test the hypothesis that STING is critically involved in AAD development by inducing SMC dedifferentiation, necroptosis and depletion. In Aim 3, we will test the therapeutic potential of targeting the ER stress-STING pathway for AAD treatment. We will test the hypothesis that pharmacologically reducing ER stress (e.g. with phenylbutyrate) or preventing STING activation (e.g. with amlexanox) will prevent SMC aortic destruction and disease progression. The proposed research is significant because it will not only provide novel molecular insights into AAD development, but also test a new therapeutic approach to prevent disease progression by reducing ER stress and blocking its detrimental response. Our study is also significant because the novel mechanisms on SMC dedifferentiation and necroptosis have broad implications in many other cardiovascular diseases. This research is innovative because it investigates the ER stress-STING pathway in AAD development, which has not been examined before. This study is a novel mechanistic investigation of necroptosis that triggers significant tissue destruction and inflammation.